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September 20, 2012

Claim that cholesterol related gene was positively selected in Africa but not elsewhere

This is one of those genetic studies whose claims are so strongly counter-intuitive that I do not know what part to believe the less. However the raw data is clearly there and that is interesting to know in any case, even if we are to systematically doubt all the claims built around that core:

AbstractLong chain polyunsaturated fatty acids (LC-PUFAs) are essential for brain structure, development, and function, and adequate dietary quantities of LC-PUFAs are thought to have been necessary for both brain expansion and the increase in brain complexity observed during modern human evolution. Previous studies conducted in largely European populations suggest that humans have limited capacity to synthesize brain LC-PUFAs such as docosahexaenoic acid (DHA) from plant-based medium chain (MC) PUFAs due to limited desaturase activity. Population-based differences in LC-PUFA levels and their product-to-substrate ratios can, in part, be explained by polymorphisms in the fatty acid desaturase (FADS) gene cluster, which have been associated with increased conversion of MC-PUFAs to LC-PUFAs. Here, we show evidence that these high efficiency converter alleles in the FADS gene cluster were likely driven to near fixation in African populations by positive selection ~85 kya. We hypothesize that selection at FADS variants, which increase LC-PUFA synthesis from plant-based MC-PUFAs, played an important role in allowing African populations obligatorily tethered to marine sources for LC-PUFAs in isolated geographic regions, to rapidly expand throughout the African continent 60–80 kya.

Whether it is true that those fatty acids are so desperately needed for bigger brains or not really so much, allow me to remain healthily skeptic to begin with (any report on elephants for example, whose diet is purely vegetarian but do have big complex brains?)

I will also remain skeptic of the fact, which is implied by the study, of a primitive vegetarian or almost vegetarian diet of Homo sapiens in Africa: I do not think that such an a priori claim can stand at all. The same logic that applies in Africa should apply in Eurasia-plus but the fact is that Eurasians retain the ancestral allele and related genetic bloc without obvious damage to the brains.

There should be another explanation therefore: for example a founder effect at the Eurasian initial "out-of-Africa" bottleneck after a process of near fixation at previous, or maybe even adaptive introgression from Neanderthals in this aspect.

Finally the authors use absolutely wrong age estimates, all founded in that nonsense as is the molecular clock. According to the authors:

Studies suggest that anatomically modern humans arose in Africa approximately 150 thousand years ago (kya), expanded throughout Africa ~60–80 kya, and to most parts of Europe and Asia ~40 kya[1]–[6].

A paper that insists in such an obvious error should never pass the peer-review process, in my not-so-humble opinion.

Even if we ignore the absurdity of this molecular-clock-o-logic pseudoscientific insistence, and accept that we have to double or more than double the age estimates to be back into the common sense zone, or better, just ignore them altogether, we still have the problem of why would the allele and the whole genetic block around it be almost fixated in Africa but not at all in that African-derived subset that is Eurasia and the smaller continents.

Figure 3. Geographic distribution of derived allele frequencies in a 100 kb region surrounding rs174537 in the 52 populations represented in the Human Genome Diversity Panel Data.Panel A represents physical position of the SNPs relative to genes in the region, Panel B is SNP name (derived allele), Panel C is frequency of derived allele (in orange) in the populations clustered based on geography, Panel D is an indication of the allele associated with increased LC-PUFA metabolism in published association studies, and Panel E is the detailed overview of rs174537 showing is near fixation within Africa.

SNPedia reports slightly less dramatic levels of fixation in Africa for rs174537 itself but nothing that is too important.

So we do have a clear case of an allele that has been selected for in Africa but, crucially, not elsewhere.

My highly skeptical questions are:

How can this have happened in Africa prior to the migration out of Africa, as the authors claim, but not affect that African subset that was the migrant "out of Africa" population, whose formation necessarily happened after the African expansion and close to the overall origin(s) of that African expansion?

If the fixated allele is so important for brain function how is it that many Eurasians-plus, who lack the allele are not plainly dumb? How did they survive along time?

Do the authors have any archaeological evidence that vegetarian sources of food, notably oils, were so extremely important in African Middle Paleolithic (Middle Stone Age)? I do not think so, not at all.

How do the authors explain the lack of selection for this allele in South Asia, a region where total or almost total vegetarianism (dairies excepted) has been very common for many millennia.

How do the authors explain the lack of selection out of Africa or even what would seem to be a tendency for the opposite selection trend in parts of East Asia and Native America?

Actually the only well known adaptive role of this SNP is that it protects against cholesterol but not the allele that appears to have been selected in Africa but the "blue bloc" that survived out if it (and may have been selected for in some regions, speculatively). TT homozygotes, and only them, have lower LDL-C and total cholesterol.These are only truly common among SE Asians and Native Americans (or Mestizos).

So what do we make of this? In truth no idea: the authors hypothesis is there but I fail to find merit in most of it. It may be just a matter of refinement of the original hypothesis however - your take.

2 comments:

"So we do have a clear case of an allele that has been selected for in Africa but, crucially, not elsewhere".

As you say, it doesn't make sense.

"We hypothesize that selection at FADS variants, which increase LC-PUFA synthesis from plant-based MC-PUFAs, played an important role in allowing African populations obligatorily tethered to marine sources for LC-PUFAs in isolated geographic regions, to rapidly expand throughout the African continent 60–80 kya."

Sounds as though the authors are totally committed to the coastal migration theory. But the idea that the Africans who gave rise to the OoA were confined to the coast doesn't make any sense either (disregarding any great southern coastal migration theory).

"How do the authors explain the lack of selection out of Africa or even what would seem to be a tendency for the opposite selection trend in parts of East Asia and Native America?"

That in itself should negate any idea of a 'coastal' migration OoA. Surely if the OoA population were confined to the coast selection in the OoA population should have been even greater.

I read more within the paper than just the intro, so I came to understand that the water resources are not obligatory, yet animal fat would be. But I may miss something, like for example fish fat being higher quality in their hypothesis.

In any case, I think that neither their base hypothesis nor the development of it they do make any sense.

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